Eotaxin, airway inflammation and hyperresponsiveness

Abstract

Eotaxin is a chemokine involved in migration and activation of inflammatory cells. CC-chemokine receptor-3 (CCR3), the receptor for eotaxin and other chemokines, is expressed by a variety of cells, such as eosinophils, Th2 cells, basophils and mast cells. These different cell types play an important role in the pathophysiology of asthma. Two characteristic features of asthma are airway inflammation, which mainly consists of increased number of eosinophils in the airway, and airway hyperresponsiveness.

This thesis aimed to assess whether eotaxin is involved in the development of airway hyperresponsiveness, either directly or indirectly via inducing eosinophil trafficking. It was investigated in three different ways.

First, it was examined whether eotaxin instillation into the airways induced airway inflammation and hyperresponsiveness. In mice eotaxin instillation into the airways did not result in increased number of eosinophils in the airways, nor did it change airway responsiveness. In contrast, eotaxin inhalation by human asthmatic volunteers resulted in a small increase in sputum eosinophils compared to placebo treatment. No changes in airway responsiveness could be measured. This might indicate that only eotaxin induced eosinophil migration under inflammatory circumstances but is not involved in the development of airway hyperresponsiveness.

Second, it was assessed whether eotaxin played a role in ovalbumin-/virus-induced airway hyperresponsiveness. Intratracheal administration of parainfluenza-3 virus to guinea pigs resulted in increased levels of eotaxin in the bronchoalveolar lavage (BAL) fluid. This coincided with increased numbers of eosinophils in the BAL fluid. In a murine model for allergic asthma, ovalbumin treatment lead to airway hyperresponsiveness, airway inflammation and increased eotaxin levels in BAL fluid. However, treatment of ovalbumin challenged and sensitised mice with anti-eotaxin antibodies did not change the number of eosinophils in the BAL fluid and airway responsiveness. Thus, although eotaxin is increasingly expressed after a respiratory virus infection or ovalbumin treatment, it seems that eotaxin is not the only factor involved in eosinophil migration.

Third, it was investigated whether eotaxin can activate mast cells. Using flowcytometry it was assessed that bone-marrow-derived mast cells express CCR3 on their surface. However, activation of this receptor by eotaxin did not influence mast cell activation. No mast cell degranulation and leukotriene C4 production could be demonstrated. Therefore, it seems unlikely that eotaxin augment inflammatory reactions by activating mast cells.

In conclusion, eotaxin alone is not responsible for increased migration of eosinophils to the airways. Only in allergic conditions, such as in asthmatic patients, eotaxin may be involved in eosinophil migration. Since anti-eotaxin antibodies did not reduce airway eosinophilia in ovalbumin treated mice, it is unlikely that eotaxin or its receptor will be a good candidate as a therapeutic target.